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Twenty crystal structures of bromodomain and PHD finger containing protein 1 (BRPF1)/ligand complexes reveal conserved binding motifs and rare interactions

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Authors:
J. Zhu; A. Caflisch

Journal: J. Med. Chem.
Year: 2016
Volume: 59
Issue: 11
Pages: 5555-5561
DOI: 10.1021/acs.jmedchem.6b00215
Type of Publication: Journal Article

Keywords:
Adaptor Proteins, Signal Transducing; Binding Sites; Crystallography, X-Ray; Humans; Ligands; Molecular Docking Simulation; Molecular Structure; Nuclear Proteins; Protein Domains; Protein Interaction Domains and Motifs; Water

Abstract:

BRPF1 plays a scaffolding role in transcription. We report on fragment screening by high-throughput docking to the BRPF1 bromodomain which resulted in six chemotypes with very favorable ligand efficiency (0.45-0.50 kcal/mol per non-hydrogen atom). Twenty crystal structures of BRPF1/ligand complexes show structural conservation in the acetyllysine binding site, common binding motifs, and unusual interactions (e.g., the replacement of a conserved water molecule). The structural information is useful for the design of chemical probes.